1-lower alkenyl-4-phenyl-4-carbonyl-piperidine derivatives and salts

ABSTRACT

D R A W I N G

United States Patent Kurt Freter Beaconsiield, Quebec, Canada;

Herbert Merz; Hans-Detlel Schroeder; Karl Zeile, all of Ingelheim, Rhine, Germany Nov. 13, 1969 Dec. 14, 1971 Boehringer lngelheim Gmbli Ingelheim am Rhine, Germany Continuation-impart of application Ser. No. 859,519, July 28, 1969, now abandoned which is a continuation 0! application Ser. No. 427,478, Jan. 22, 1965, now abandoned. This application Nov. 13, 1969, Ser. No. 876,570

[72] inventors [2i Appl. No. [22] Filed [45] Patented [73] Assignee [54] l-LOWER ALKENYL-4-Pl-lENYL-4-CARBONYL- PIPERIDINE DERIVATIVES AND SALTS 7 Claims, No Drawings 52 vs. Cl 260/294L3 E,

' 260 2934 A, 260/294.7 .l, 360 2943 A, 260/456 P, 260/583 0, 260/293 E, 260/294 s,

424/267 [5 l Int. Cl C07d 29/24 [50] Field of Search 260/294.7

J, 294.3 X, 293.4], 294.3 A

J. Am. Pharm. Assoc. Vol. 39, pages 245, 247- 248, May 1950, Eddy Bull. Wld. Hlth. Org, Vol. 13, pages 937, 957- 964, i955, Braenden et al.

Endeavour, Vol. 23, pages 97- 10!, May 1964, Bentley 1. Chem. Soc., 1948, pages 559- 561, Thorp et al.

Primary Examiner-Henry R. J iles Assistant Examiner-S. D. Winters Attorney-Hammond & Littell ABSTRACT: Compounds of the formula provided, however, that when X is -CH CH= OHCl,

R is other than ethyl and R is other than 3-hydroxyl, and non-toxic, pharmacologically acceptable acid addition stalts thereof, useful as morphine-antgonistic analgesics.

1 -LOWER ALKENYL-4-PHENYL-4-CARBONYL PIPERIDINE DERIVATIVES AND SALTS This is a continuation-in-part of copending application Ser. No. 859,519, filed July 28, 1969, now abandoned, which in turn is a continuation of copending application Ser. No. 427,478, filed Jan. 22, 1965, now abandoned.

This invention relates to novel l-lower alkenyl-4-phenyl-4 carbonyl-piperidine derivatives and acid addition salts thereof, as well as to various methods of preparing these compounds.

More particularly, the present invention relates to compounds of the formula METHOD A By reacting a secondary piperidine derivative of the formula wherein R,, R and R, have the same meanings as in fonnula l, with a lower alkene derivative of the formula Z --X In wherein X has the same meanings as in formula I and Z is halogen or p-toluene sulfonyloxy.

The reaction is preferably carried out in the presence of a suitable inert organic solvent and of a weak base, such as sodium bicarbonate, at a temperature between 50 and C. The reactants may be used in a molar ratio of 1:], but it is preferred to provide an excess of the lower alkene derivative lll. Preferred inert organic solvents are lower alkanols or a mixture of dimethyl formamide and tetrahydrofuran.

In the preparation of N-haloalkenyl-piperidines of the formula l by this method the halo-substituted lower alkene derivative lll may be a mixture of the cisand transstereoisomers, or it may be the pure cisor trans-stereoisomer. In the event that starting compound II] is a mixture of the stereoisomers, the end product of the formula I will also be a mixture of the cisand trans-stereoisomers which may, if desired, subsequently be separated into its pure stereoisomeric components by customary methods, such as by crystallization. On the other hand, if the starting compound [II is the pure cisor trans-stereoisomer, the end product 1 will be the corresponding pure cisor trans-N-ha.loalkenyl-piperidine derivative, respectively.

METHOD B By reacting a di-(B-haloethyU-lower alkenyl-amine of the formula wherein R, and X have the same meanings as in formula I and Hal is a halogen, with a benzyl cyanide of the formula wherein R has the same meanings as in formula I, to form an intermediate l-lower alkenyl-4-cyano-4-phenyl-piperidine compound of the formula wherein R R and X have the same meanings as in formula I, and thereafter converting the 4-cyano group of said intermediate Vl into an ester or keto group of the formula wherein R has the same meanings as in formula I, by conventional methods.

The ring closure reaction between compounds IV and V is carried out in the presence of a suitable condensation catalyst, such as sodium amide, and of an inert organic solvent, such as toluene, at a temperature between 40 and 200 C.

ln order to convert the 4-cyano group in intermediate compound Vl into an alkoxycarbonyl group, i.e. to obtain an end product of the formula I wherein R is alkoxy, the intermediate 4-cyano-piperidine compound is first hydrolized with an aqueous acid or alkali, and the 4-carboxyl hydrolysis product is then esterified with the desired alkanol.

For conversion of the intermediate 4-cyano compound Vl into an end product of the formula I wherein R: is alkyl, the intermediate compound Vl is first reacted with a corresponding Grignard reagent in the presence of a suitable organic solvent, and the 4-ketimine formed thereby is subsequently hydrolized.

lf R in the end product of the formula I is to be a hydroxyl group, it is necessary to protect the analogous hydroxyl substituent in the benzyl cyanide V by acylation or alkylation prior to subjecting compound V to the ring closure condensation reaction with compound IV. The deacylation of a hydroxyl group thus protected takes place automatically and simultaneously with the acid or alkaline hydrolysis of the cyano group of the intermediate VI or with the hydrolysis of the ketimine intermediate in the preparation of a 4-keto compound (R =alkyl) of the formula I.

If the phenyl ring in the cyano compound Vl comprises a hydroxyl substituent which has been protected with an alkyl radical, it is advantageous to effect the hydrolysis of the cyano group or the ketimine group with the aid of hydrobromic acid or hydroiodic acid, because the protective alkyl group is simultaneously split off thereby.

A hydroxyl substituent attached to an end product of the formula I obtained by Method A or B above may, if desired, be subsequently methylated or acylated and, conversely, a methoxy group or acetyl group attached to the phenyl moiety may subsequently be demethylated or hydrolized, respectively, all by conventional methods.

The N-lower alkenyl-piperidine derivatives of the formula 1 above are bases and, therefore, form nontoxic acid addition salts with inorganic and organic acids. Such acid addition salts are obtained by conventional methods; for example, by dissolving the free base in a suitable solvent and acidifying the solution with one or more molar equivalents of the desired acid. Examples of nontoxic, pharmacologically acceptable acid addition salts of the N-lower alkenyl-piperidine derivatives according to the present invention are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, tartaric acid, fumaric acid, maleic acid, citric acid, ascorbic acid, caproic acid, propionic acid, 8-chlorotheophylline and the like.

Examples of specific N-lower alkylene-piperidine derivatives of the formula I, stereoisomers and stereoisomeric mixtures thereof, and their nontoxic, pharmacologically acceptable acid addition salts, especially the hydrochlorides, which may be prepared by the methods described above are the fol lowing:

piperidine.

(2) Trans- 1 3 '-chloroallyl )-4-( 3 -methylphenyl) -4-ethoxycarbonyl-piperidine.

(3) Trans- 1 3 '-chloroallyl )-4-( 2 '-chlorophenyl) propionyl-piperidine.

(4) l-( 3 -chloroallyl )-4-( 3 '-chlorophenyl )-4-methoxyearbonyl-piperidine.

(5) l-( 3 "chloroallyl)-4-( 3 '-chlorophenyl)-4-ethoxycarbonyl-piperidine.

(6) l-( 3 '-chloroallyl )-4-( 4' '-chlorophenyl )-4-propionylpiperidine.

(7) l-(3'-chloroallyl)-4-(4"-chlorophenyl)-4-methoxycarbonyl-piperidine.

1-3 '-chloroallyl )-4-( 2' '-methylphenyl )-4-acetyl- (8) l-( 2 '-bromoallyl )-4-( 4' -chlorophenyl)-4-propionylpiperidine.

(9) l-( 3 3 -dichloroallyl )-4-( 3 -methylphenyl) -4- methoxycarbonyl-piperidine.

10) l-( 3 '-chloroallyl )-4-( 3 -hydroxyphenyl )-4-acetylpiperidine.

l l) l-(3'-chloroallyl)-4-( 3"-hydroxyphenyl)-4-methoxycarbonyl-piperidine.

12) l-( 3 '-chloroallyl )-4-( 3 '-hydroxyphenyl )-4- ycarbonyLpiperidine.

ethoxmethoxycarbonyl-piperidine.

(17) l-( 3 3 -dirnethylallyl)-4-( 3 4' -dimethylphenyl )-4- propionyl-piperidine.

l 8) l-( 3 3 -dimethylallyl )-4-( 3 '-chlorophenyl -4- methoxycarbonyl-piperidine.

( l9 1-( 3 3 -dimethylallyl)-4-(4' '-chlorophenyl -4- propionyl-piperidine.

(20) 1-( 2'-methylallyl )-4-( 4' '-methylphenyl )-4-ethoxycarbonyl-piperidine.

(21) l-( 2'-mcthylallyl )-4-( 3 '-bromophenyl )-4-acetylpiperidine.

(22) l-( 2 '-methylallyl )-4-( 3 '-chlorophenyl )-4-propiony|- piperidine.

(23) l-( 2-methylallyl )-4-( 3 -chlorophenyl )-4-ethoxycarbonyl-piperidine.

(24) 1-( 2'-methylallyl )-4-( 4 '-chlorophenyl )-4-propionylpiperidine.

(25) l-( 2'-methylallyl )-4-( 4' '-chlorophenyl )-4-methoxycarbonyl-piperidine.

(26) 1-( 2'-methylallyl )-4-( 4 '-chlorophenyl )-4-ethoxycarbonyl-piperidine.

(27) 1-(2'-methylallyl)4-(3"-fluorophenyl)-4-methoxycarbonyl-piperidine.

(28) l-( l'-methylallyl)-4-(3"-methylphenyl)-4-ethoxycarbonyl-piperidine.

(29) l-(3', 3"dimethylallyl)-4-(3"-hydroxyphenyl) -4- acetyl-piperidine.

(30) l-(3', 3'-dimethylallyl)-4-(3"-hydroxyphenyl) -4- propionyl'piperidine. (31 l-(3', 3-dimethylallyl)-4-( 3"- hydroxyphenyl) -4-methoxycarbonyl-piperidine.

(32) l-(3, 3'-dimethylallyl)-4-(3"-hydroxyphenyl) -4- ethoxycarbonyl-piperidine.

(33) l-( 3 3 '-dimethylallyl-3a-methyl-4-( 3 -hydroxyphenyl)-4-propionyl-piperidine.

(34) l-( 3', 3'-dimethylallyl)-3a-methyl-4-( 3 -hydroxyphenyl)-4-methoxycarbonyl-piperidine.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

The absence of the prefix trans" or cis from the nomenclature of those starting compounds or end products existing in stereoisomeric forms in the following examples as well as in the preceding list of compounds which may be prepared by Methods A and B signifies that a mixture of stereoisomers was used or obtained.

EXAMPLE 1 Preparation of l-(3'-chloroallyl)-4-(2"-methylphenyl)-4- acetyl-piperidine hydrobromide by Method A 2.65 g. of 4-(2'-methylphenyl)-4-acetylpiperidine hydrobromide were dissolved in 10 cc. of water, the solution was admixed with 10 cc. of 2 N sodium hydroxide, and the resulting alkaline aqueous mixture was extracted with ether. The ethereal phase was separated, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in a mixture of 30 cc. tetrahydrofuran and 15 cc. dimethylformamide, and the solution was admixed with 1.3 g. of 1,3- dichloropropene-(Z) and 1.5 g. of sodium carbonate. The

resulting mixture was refluxed for 7 hours and thereafter evaporated to dryness in an aspirator vacuum, the residue was extracted with chloroform, the chloroform solution was dried and then evaporated, the residue was dissolved in methylene chloride containing 2 percent ethylacetate, and the solution was filtered through 60 g. of basic aluminum oxide (activity I). The solvent was then evaporated, the residue was taken up in about 5 cc. of methanol, and the solution was made weakly acid with ethereal hydrobromic acid. Thereafier, ether was added to the solution until it turned slightly cloudy, whereby a crystalline precipitate separated out, which was separated and recrystallized from a mixture of methanol and ether. 2.4 g. (62 percent of theory) of a compound having a melting point of l80-l82 C. were obtained. It was identified to be l-(3'- chloroallyl)-4-(2"-methylphenyl)-4-acetyl-piperidine hydrobromide of the formula EXAMPLE 2 Preparation of l-(3-chloroallyl)-4-(3"-hydroxyphenyl)-4- acetyl-piperidine hydrochloride by method A 2.18 g. (0.010 mol) of 4-(3-hydroxyphenyl)-4-acetylpiperidine, 1.26 g. (0.0l5 mol) of sodium bicarbonate, 1.23 g. (0.01l mol) of 1,3-dichloropropene-(2), cc. of dimethylformamide and 25 cc. of tetrahydrofuran were admixed with each other, and the mixture was refluxed for 2 hours. Thereafter, the solvent medium was evaporated in vacuo, and the residue was rinsed with 50 cc. of chloroform into a separating funnel. The chloroform solution was shaken three times with 20 cc. portions of water, dried over sodium sulfate and then evaporated in vacuo. The residue was taken up in methanol, the resulting solution was acidified with 4 cc. of 2.5 N ethanolic hydrochloric acid, and the acid solution was admixed with ether until it turned cloudy. Upon scratching, a precipitate formed, the mixture was allowed to stand overnight, the precipitate was separated by vacuum filtration, washed with ether and dried. l.8 g. (54.5 percent of theory) of a compound having a melting point of 184 C. (recrystallized from a mixture of methanol and ether) were obtained. It was identified to be l-(3-chloroallyl) -4-(3"-hydroxyphenyl)-4- acetyl-piperidine hydrochloride of the formula EXAMPLE 3 Preparation of transl 3 -chloroa.llyl)-4-( 3 '-hydroxyphenyl) -4-methoxycarbonyl-piperidine hydrochloride by method A 5.44 g. (0.02 mol) of 4-(3-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride, 4.2 g. (0.05 mol) of sodium bicarbonate, 2.46 g. (0.022 mol) of trans-1,3- dichloropropene-(Z), 10 cc. of dimethylformamide and 25 cc. of tetrahydrofuran were admixed with each other, and the mixture was refluxed for 2 hours. Thereafter, the solvent medium was evaporated in vacuo, and the residue was rinsed with 50 cc. of chloroform into a separating funnel. The chloroform solution was extracted three times with 20 cc. portions of water, then dried over sodium sulfate and evaporated in vacuo. The residue was taken up in methanol, the resulting solution was acidified with 4 cc. of 2.5 N ethanolic hydrochloric acid, and the acid solution was admixed with ether until it turned cloudy. lt was allowed to stand overnight, and then the crystalline precipitate which had formed was filtered off. 5.9 g. (74.5 percent of theory) of a compound having a melting point of 2l7-2l8 C. (recrystallized from a mixture of methanol and ether) were obtained. It was identified to be transl 3'-chloroallyl)-4-( 3 -hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride of the. formula l CHz-CH=CHC1 EXAMPLE 4 Preparation of cisl-( 3'-chloroallyl)-4-( 3 -hydr0xyphenyl) -4methoxycarbonyl-piperidine hydrochloride by method A 5.44 g. (0.02 mol) of 4-(3'-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride, 4.2 g. (0.05 mol) of sodium bicarbonate, 2.46 g. (0.022 mol) of cis-l,3-dichloropropene- (2), 10 cc. of dimethylformamide and 25 cc. of tetrahydrofuran were admixed with each other, and the mixture was refluxed for 2 hours. Thereafter, the solvent medium was evaporated in vacuo, and the residue was rinsed with 50 cc. of chloroform into a separating funnel. The chloroform solution was extracted three times with 20 cc. portions of water, then dried over sodium sulfate, and finally evaporated in vacuo. The residue was taken up in methanol, the resulting solution was acidified with 4 cc. of 2.5 N ethanolic hydrochloric acid, and the acid solution was admixed with ether until it turned cloudy. lt was then allowed to stand overnight, and the crystalline precipitate formed thereby was filtered off. 6.1 g. (77 percent of theory) of cis-l-(3'-chloroallyl)-4-(3"-hydroxyphenyl)-4-methoxy carbonyl-piperidine hydrochloride, m.p. l97l98 C. (recrystallized from a mixture of methanol and ether), were obtained.

EXAMPLE 5 Preparation of 1-(3'-chloroallyl)-4-(3"-hydroxyphenyl)-4- ethoxycarbonyl-piperidine hydrochloride by method A 2.86 g. (0.01 mol) of 4-(3hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, 2.10 g. (0.025 mol) of sodium bicarbonate, 1.23 g. of 1,3-dichloropropene-(2), 10 cc. of dimethylformamide and 25 cc. of tetrahydrofuran were admixed with each other, and the mixture was refluxed for 2 hours. Thereafter, the solvent medium was evaporated in vacuo, and the residue was rinsed with 50 cc. of chloroform into a separating funnel. The chloroform solution was extracted three times with 20 cc. portions of water, dried over sodium sulfate and evaporated in vacuo. The residue was taken up in methanol, the resulting solution was acidified with 4 cc. of 2.5 N ethanolic hydrochloric acid, and the acid solution was admixed with other until it turned cloudy. 2.3 g. (64 percent of theory) of a compound having a melting point of 207 C. (recrystallized from a mixture of ethanol and ether) were obtained. It was identified to be l-(3 -chloroallyl)-4-(3 "-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride of the fonnula CHPCH=CHC1 EXAMPLE 6 Preparation of l-(3-chloroallyl)-4-(3"-methoxypheny1)-4- ethoxycarbonyl-piperidine hydrochloride l 3.74 g. (0.01 mol) of l-(3'-chloroallyl)-4-(3"-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride (the end product of example 5) were shaken in a separating funnel with a mixture consisting of 50 cc. of chloroform, 25 cc. of water and cc. of 2 N aqueous ammonia. The chloroform phase was then separated, washed with 25 cc. of water, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 25 cc. of tetrahydrofuran, and the resulting solution was admixed with a solution of 0.0l25 mol of diazomethane in ether. After 4 hours of standing the solvent medium was evaporated, the residue was taken up in chloroform, the resulting solution was washed twice with 2 N sodium hydroxide and then with water, dried over sodium sulfate, the chloroform was evaporated, the residue was dissolved in cc. of ethanol, and the resulting solution was acidified with 4 cc. of 2.5 N ethanolic hydrochloric acid. The acid solution was thereafter admixed with ether until it turned cloudy. 2.5 g.

(64.5 percent of theory) of a compound having a melting point of l6l.5 C. (recrystallized from a mixture of ethanol andether) were obtained..lt was identified to be 1-(3'- chloroallyl)-4-(3"-methoxyphenyl)-4-ethoxycarbonylpiperidine hydrochloride ofthe formula OHIO EXAMPLE-7 Preparation of cis-l-(3-chloroallyl)4-(3"-acetoxyphenyl) -4-methoxycarbonyl-piperidine hydrochloride 4.5 g. (0.013 mol) of,cis-l-(3'-chloroal1yl)-4-3"-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride (the end product of Example 4) were dissolved by stirring in a mixture consisting of 50 cc. of absolute pyridine and 5 cc. of

acetic acid anhydride (which took about 10 minutes), and the resulting solution was allowed to stand for 12 hours at room temperature under exclusion of moisture. Thereafter, the

over sodium sulfate, and evaporated in vacuo. The residue was dissolved in 50 cc. of absolute ether, and the resulting solution was acidified 7 cc. of 2.5 N ethanolic hydrochloric acid. The crystalline precipitate formed thereby was separated by vacuum filtrationand washed with absolute ether. 4.9 g. (97 percent of theory) of a compound having a melting point of 173 C. (recrystallized from a mixture of methanol and ether).

were obtained. lt was identified to be cis-l-(3'-chloroally1)-4 (3"-acetoxyphenyl)- 4-methoxycarbonyl-piperidine hydrochloride of the formula Using a procedure analogous to that described in example 1, l-( 3'-chloroallyl)-4-(2' -methylphenyl )-4-propionylpiperidine hydrochloride, m.p. 2152l7 C., of the formula 0 Hi-CIHJ was prepared from 4-(2-methylphenyl)-4-propionylpiperidine hydrochloride and 1,3-dich|oropropene-( 2). The yield was 2.0 g. (58 percent of theory).

EXAMPLE 9 Using a procedure analogous to that described in example 1, 1-(3'-chloroallyl)-4-(3"-rnethylphenyl)-4-acetyl-piperidine hydrochloride, m.p. 208-2 10 C., was prepared from 4-(3" methylphenyl)-4-acetyl-piperidine hydrochloride and 1,3- dichloropropene-(2). The yield was 2.2 g. (67 percent of theory).

EXAMPLE 10 Using a procedure analogous to that described in example 1 l-( 3 -chloroallyl).-4-( 3f @methylphenyl )-4-propionylpiperidine hydrochloride, m.p. 204-207 C., was prepared from 4-( 3 '-methylphenyl )-4-propionyl-piperidine hydrochloride and 1,3-dichloropropene-(2) (reflux time: I 1.5 hour's)..'lhe yield was 2.0 g. (56 percent of theory).

EXAMPLE 1 l Using a procedure analogous to that described in example 1, l-(3'-chloroally1)-4-(3"-methylphenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. l95"196 C., was prepared from 4-(3'-methylphenyl)-4-methoxycarbonyl-piperidine hydrochloride and 1,3-dichloroprbpene-(2) (reflux time: 1 1.5 hours). The yield was 2.0 g. (58 percent of theory).

EXAMPLE 12 Using a procedure analogous to that described in example 1 transl 3 '-chloroallyl)-4 3 '-methylphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 209 2l 1 C., was prepared from 4-(3f-methylphenyl)-4-ethoxycarbonylpiperidine hydrochloride and trans-1,3-dichloropropene-(2) (reflux time: 9 hours). The yield was 1.9 g. (53 percent of theory).

EXAMPLEv l 3 Using a procedure analogous to that described in example 1 cis'- l-( 3 '-ch1oroal1yl)4-( 3"-methylpheny1)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 140-l42 C., was prepared from 4-(3-methylphenyl)-4-ethoxycarbonylpiperidine hydrochloride and cis-1,3-dichloropropene-(2) (reflux time: 9 hours). The yield was 2.5 g. (70 percent of theory).

EXAMPLE 14 Using a procedure analogous to that described in example 1 l-( 3'-chloroallyl)-4-(4"-methylphenyl)-4-acetyl-piperidine hydrochloride, mp. 22 l225 C., of the formula CHa i i] i (Tr-CH3 N l C Ha-CH=CHC1 was prepared from 4-(4-methylphenyl)-4-acetyl-piperidine hydrochloride and 1,3-dichloropentene-(2). The yield was 1.5 g. (46 percent of theory).

EXAMPLE Using a procedure analogous to that described in example 1 1-( 3 '-chloroallyl)-4-(4' -methylphenyl)-4-propionylpiperidine hydrochloride, m.p. 223-228 C., was prepared from 4-(4'-methylphenyl)-4-propionyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.8 g. (53 percent of theory);

EXAMPLE 16 Using a procedure analogous to that described in example 1, l-( 3 '-chloroallyl)-4-(4 '-methylphenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 201-203 C., was prepared from 4-(4'-methylphenyl)-4-methoxycarbonyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 2.1 g. (61 percent of theory).

EXAMPLE 17 Using a procedure analogous to that described in example 1 l-( 3 '-chloroallyl )-4-( 4' '-methylphenyl)-4-ethoxycarbonylpiperidine hydrochloride, m.p. 194-l97 C., was prepared from 4-(4'-methylphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.8 g. (50 percent of theory).

EXAMPLE 18 Using a procedure analogous to that described in example l transl 3 '-chloroallyl )-4-( 2 -chlorophenyl )-4-acetylpiperidine hydrochloride, m.p. l92-l93 C., of the formula was prepared from 4-(2'-chlorophenyl)-4-acetyl-piperidine hydrochloride and trans-1,3-dichloropropene-(2). The yield was 3.2 g. (92 percent oftheory).

i9 EXAMPLE 19 Using a procedure analogous to that described in example 1, transl 3 -chloroallyl )-4-( 2 '-chlorophenyl )-4-propionylpiperidine hydrochloride, m.p. 2l7-2l8 C., was prepared from 4-(2'-chlorophenyl)-4-propionyl-piperidine hydrochloride and trans-1,3-dichloropropene-(2). The yield was 1.2 g. (33 percent oftheory).

EXAMPLE 20 Using a procedure analogous to that described in example 1 l-( 3 '-chloroallyl )-4-( 3 '-chlorophenyl )-4-acetyl-piperidine hydrochloride, m.p. l92-l93 C., of the formula EXAMPLE 21 Using a procedure analogous to that described in example 1, l-( 3 '-chloroallyl)-4-( 3 '-chlorophenyl)-4-propionylpiperidine hydrochloride, m.p. 238-239 C., was prepared from 4-( 3 '-chlorophenyl) 4-propionyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.8 g. (50 percent of theory).

EXAMPLE 22 Using a procedure analogous to that described in example 1, l-(3'-chloroallyl)-4-(3"-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. l95-l97 C., was prepared from 4-( 3 '-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.8 g. (49 percent of theory).

EXAMPLE 23 Using a procedure analogous tothat described in example 1, l-( 3-chloroallyl )-4-( 3 '-chlorophenyl )-4-ethoxycarbonylpiperidine hydrochloride, m.p. 21l-2l3 C., was prepared from 4-( 3 '-chlorophenyl )-4-ethoxycarbonyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.9 g. (50 percent of theory).

EXAMPLE 24 Using a procedure analogous to that described in example 1, l-(3'-chloroallyl)-4-(4"-chlorophenyl)-4-acetyl-piperidine hydrochloride, m.p. l98-200 C., of the formula was prepared from 4-(4'-chlorophenyl)-4-acetyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.9 g. (55 percent of theory).

EXAMPLE 25 Using a procedure analogous to that described in example 1 l-( 3'-chloroallyl)-4-(4' '-chlorophenyl)-4-propionylpiperidine hydrochloride, m.p. 225-256 C., was prepared from 4-(4-chlorophenyl)-4-propionyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 1.5 g. (41 percent of theory).

EXAMPLE 26 Using a procedure analogous to that described in example l, l-( 3 -chloroallyl )-4( 4' '-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. l99-200 C., was prepared from 4-( 4'-chlorophenyl )-4-methoxycarbonyl-piperidine hydrochloride and l,3-dichloropropene-(2). The yield was 2.0 g. (55 percent of theory).

EXAMPLE 27 Using a procedure analogous to that described in example 1 l-( 3 '-chloroallyl)-4-(4' '-chlorophenyl)-4-ethoxycarbonylpiperidine hydrochloride, m.p. 2l922l C., was prepared from 4-(4-chlorophenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 1,3-dichloropropene-(2). The yield was 2. l g. (55 percent oftheory).

EXAMPLE 28 Using a procedure analogous to that described in example 1 l-( 2'-chloroallyl)-4-( 3 "-chlorophenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. l94-l96 C., of theformula -HCl was prepared from 4-(3'-chlorophenyl)-4-methoxycarbonylpiperidine hydrochloride and l-bromo-2-chloropropene-(2) (reflux time: 3 hours). The yield was 3.5 g. (96 percent of theory).

EXAMPLE 29 Using a procedure analogous to that described in example 1, l 2-bromoallyl)-4-( 2' '-methylphenyl)-4-acetyl-piperidine hydrobromide, m.p. 209-2l 1 C., of the formula CHa- 12 was prepared from 4-(2'-methylphenyl)-4-acetyl-piperidine hydrochloride and 1,3-dibromopropene-(2) (reflux time: 2.5 hours). The yield was 3.2 g. (77 percent of theory).

EXAMPLE 30 Using a procedure analogous to that described in example 1 1-( 2'-bromoallyl )-4-( 3 '-methylphenyl)-4-acetyl-piperidine hydrobromide, m.p. l87-l89 C., was prepared from 4-(3'- methylphenyl)-4-acetyl-piperidine hydrochloride and 1,3- dlbromopropene-(2) (reflux time: 2.5 hours). The yield was 2.2 g. (53 percent of theory).

EXAMPLE 3] Using a procedure analogous to that described in example i l-( 2'-bromoallyl )4-( 3 -methylphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. 203-204 C., was prepared from 4-( 3 -methylphenyl )-4-methoxycarbonyl-piperidine hydrochloride and l,3-dibromopropene'(2) (reflux time: 2.5 hours). The yield was 3.1 g. (80 percent of theory).

EXAMPLE 32 Using a procedure analogous to that described in example 1, 1-( 2-bromoallyl )-4-( 3 -methylphenyl )-4-ethoxycarbonylpiperidine hydrochloride, m.p. l77-l78 C., was prepared from 4-(3'-methylphenyl)-4g. hydrochloride and 1,3- dibromopropene-(2) (reflux time: 2.5 hours). The yield was 3.9 g. (97 percent of theory).

EXAMPLE 33 Using a procedure analogous to that described in example, I ,1-(2'-bromoallyl)-4-(4'-'-methylphenyl)4-acetyl-piperidine hydrobromide, m.p. 229-23l C., was prepared from 4-(4 methylphenyl)-4-acetyl-piperidine hydrochloride and 1,3- dibromopropene-(2) (reflux time: 2.5 hours). The yield was 3.5 g. (84 percent of theory).

EXAMPLE 34 Using a procedure analogous to that described in example 1, l-(2'-bromoallyl)-4-(4' '-methylphenyl)-4-methoxycarbonyl-piperidine hydrobromide, m.p. 2l52 1 7 C., was prepared from 4-(4'-methy1phenyl )-4-methoxycarbonyl-piperidine hydrochloride and 1,3-dibromopropene-(2) (reflux time: 2.5 hours). The yield was 3.0 g. (69 percent of theory).

EXAMPLE 35 Using a procedure analogous to that described in example 1 l-( 2'-bromoallyl )-4-( 3 '-chlorophenyl )-4-acetyl-piperidine hydrobromide, m.p. 206-208 C., was prepared from 4-(3'- chlorophenyl)-4-acetyl-piperidine hydrochloride and 1,3- dibromopropene-2) (reflux time: 2.5 hours). The yield was 3.6 g. (82 percent of theory).

EXAMPLE 36 Using a procedure analogous to that described in example 1 1-( 2'-bromoallyl )-4-( 3 '-chlorophenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. l93195 C., was prepared from 4-( 3 '-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride and l,3-dibromopropene-( 2) (reflux time: 2.5 hours). The yield was 4.0 g. (98 percent of theory).

EXAMPLE 37 .1}... l4 EXAMPLE 38 EXAMPLE 43 Using a procedure analogous to that described in example Using a procedure analogous to that described in example 1, 1-(2'-bromoallyl)-4-(4"-chlorophenyl)-4-methoxycarbonr y y yph y )-4- yrylyl-piperidine hydrochloride, m.p. 209-210 C., was prepared 5 piperidine hydrochloride -P- Of the formula from 4-(4'-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride and 1,3-dibromopropene-(2) (reflux time: 2.5 H0- hours). The yield was 3.5 g. (86 percent of theory). (I)

EXAMPLE 39 -HC1 Using a procedure analogous to that described in example 1, l-(3', 3'-dichloroallyl)-4-(3"-methylphenyl)-4-acetylpiperidine hydrochloride, m.p. 235-238 C., of the formula N i CHB dU-la-LH-CIICI 0 was prepared from 4-(3'-hydroxyphenyl)-4-butyryl-piperidine L CH and 1,3-dichloropropene-(2). The yield was 2.1 g. (57 percent H01 of theory).

EXAMPLE 44 Using a procedure analogous to that described in example N 5, l-( 3'-chloroallyl )-4-( 3 -hydroxyphenyl )-4-propoxycardHl-CH=O I bonyl-piperidine hydrochloride, m.p. l98 C., was prepared 1 from 4-( 3 '-hydroxyphenyl )-4-propoxycarbonyl-piperidine hydrochloride and l,3-dichloropropene-( 2). The yield was 2.4 was prepared from 4-(3'-methylpheyl)-4-acetyl-piperidine g- P n ofth ry). hydrochloride and l,3,3-trichloropropene-(2) (reflux time: 3

hours). The yield was 3.0 g. (83 percent of theory). EXAMPLE 45 Using a procedure analogous to that described in example EXAMPLE 40 5, l-( 3-chloroallyl)-4-( 3"-methoxyphenyl)-4'propionyl- Using a procedure analogous to that described in example piperidine hydrochloride, -P- Ofthe formula l,l-(3', 3-dichloroallyl)-4-(3"-methylphenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 2l8-2l9 C., was prepared from 4-(3-methylphenyl)-4-methoxycarbonylpiperidine hydrochloride and 1,3,3-trichloropropene-(2) (43,11 (reflux time: 3 hours). The yield was 3.7 g. (98 percent of theory). 40

EXAMPLE 4] L -HO1 Using a procedure analogous to that described in example 1, l-(3, 3'-dichloroallyl)-4-(3"-chlorophenyl)-4-methox- 7 H H u Adam g V ycarbonyl-piperidine hydrochloride, m.p. 224-225 C., was was p ep r fr m '-m h yph yl)- -pr pi nylprepared from 4-(3'-chl0r0phenyl)-4-meth0xycarbonylpiperidine hydrochloride and 1,3-dichloropropene-(2). The piperidine hydrochloride and l,3,3-trichloropropene-(2) Yleld was 8- F oftheofyl (522:5) time: 3 hours). The yield was 3.0 g. (75 percent of EXAMPLE 46 Using a procedure analogous to that described in example EXAMPLE 42 5, l-(3'-chloroallyl)-4-(3"-methoxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 161.5 C., was prepared from 4-( 3 -methoxyphenyl )-4-ethoxycarbonyl-piperidine hydrochloride and l,3-dichloropropene-(2). The yield was 2.3 g. (61.5 percent oftheory).'

Using a procedure analogous to that describe in example, I, l-(3, 3'-dibromoallyl)-4-(3 "-chlorophenyl)-4 -methoxycar- 5 bonyl-piperidine hydrobromide, m.p. 230-232 C., of the formula EXAMPLE 47 Using a procedure analogous to that described in example 0 7, trans- 1-( 3 '-chloroallyl )-4-( 3 '-acetoxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. 194 C., of the for- -HBr mula (H) N Br Cilia-'0 JHrCH=C h C-OCHa was prepared from 4-(3'-chlorophenyl)-4-methoxycarbonylpiperidine hydrobromide and 1,3,3-tribromopr0pene-(2) o (reflux time: 3 hours). The yield was 4.9 g. (92 percent of N was prepared from 4-( 3 -hydroxyphenyl)-4-methoxycarbonylpiperidine hydrochloride and acetic acid anhydride. The yield was 4.9 g. (97 percent oftheory).

EXAMPLE 48 Using a procedure analogous to that described in example 5 l 3 'chloroallyl)-4-( 2' '-hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. 230 C., of the formula jiEzQEeEEQL a.

was prepared from 4-(2-hydroxypheny)-4-methoxycarbonylpiperidine hydrochloride and l,3-dichloropropene-( 2). The yield was 2.0 g. (56 percent of theory).

-CH1 L 4101 was prepared from 3a-methyl-4-(3"-hydroxyphenyl)-4- propionyl-piperidine and 1,3-dichloropropene-(2). The yield was 1.8 g. (50 percent oftheory).

EXAMPLE 51 Using a procedure analogous to that described in example 4, cisl-( 3 '-chloroallyl)-3a-methyl-4-( 3 '-hydroxyphenyl)-4- methoxycarbonyl-piperidine hydrochloride, m.p. l25-2l8 C., was prepared from 3a-methyl-4-(3'-hydroxyphenyl)-4- methoxycarbonyl-piperidine hydrochloride and cis-l,3- dichloropropene-(2). The yield was 2.0 g. (55.5 percent of theory).

EXAMPLE 5 2 Using a procedure analogous to that described in example 3, transl 3 '-chloroallyl)-3a-methyl-4-( 3 '-hydroxyphenyl 4-methoxycarbonyl-piperidine hydrochloride, m.p. l54l58 C., was prepared from 3a-methyl-4-(3'-hydroxyphenyl)-4- methoxycarbonyl-piperidine hydrochloride and trans-1,3- dichloropropene-(Z). The yield was 2.3 g. (64 percent of theory).

NEXAMELEQLW Using a procedure analogous to that described in example 3, transl 3 '-chloroallyl)-3a-methyl-4-( 3 '-hydroxyphenyl 4-methoxycarbonyl-piperidine hydrochloride, m.p. l00l03 C., was prepared from 3a-methyl-4-(3'-hydroxyphenyl)-4- methoxycarbonyl-piperidine hydrochloride and trans-1,3- dichloropropene-(Z). The yield was 2.5 g. (69.5 percent of theory).

EXAMPLE 54 Using a procedure analogous to that described in example 4, cisl 3 '-chloroallyl )-3fi-methyl-4-( 3 -hydroxyphenyl )-4- methoxycarbonyl-piperidine hydrochloride, m.p. -95 C., was prepared from 3B-methyl-4-(3'-hydroxyphenyl)-4- methoxycarbonyl-piperidine hydrochloride and cis-l,3- dichloropropene-(2). The yield was 2.0 g. (55.5 percent of theory).

EXAMPLE 55 Using a procedure analogous to that described in example 2, l-( 2-chloroallyl )-4-( 3 '-hydroxyphenyl )-4-acetylpiperidine hydrochloride, m.p. C., of the formula was prepared from 4-(3'-hydroxyphenyl)-4-acetyl-piperidine and 2,3-dichloropropene-( l The yield was 2.6 g. (69 percent of theory).

EXAMPLE 56 Using a procedure analogous tov that described in example 2, l-(2'-chlor0allyl)-4-(3"-hydroxyphenyl)-4-propionylpiperidine hydrochloride, m.p. 183 C., was prepared from 4- (3 -hydroxyphenyl)-4-propionyl-piperidine and 2 ,3- dichloropropene-( l The yield was 2.4 g. (70 percent of theory).

EXAMPLE 57 Using a procedure analogous to that described in'example 5 l-( 2-chloroallyl )-4-( 3 -hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. 181 C., was prepared from 4-(3'hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride and 2,3-dichloropropene-( l The yield was 2.5 g. (72 percent of theory).

EXAMPLE 5 8 Using a procedure analogous to that described in example 5 l-(2chloroallyl)-4-( 3 'hydroxyphenyl-4-ethoxycarbonylpiperidine hydrochloride, m.p. l89.5 C., was prepared from 4-(3'-hydroxypnenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 2,3-dichloropropene-( l The yield was 3.0 g. (83.5 percent of theory).

EXAMPLE 59 Using a procedure analogous to that described in example 2, l-( 3 ,3 -dichloroallyl )-4-( 3 -hydroxyphenyl )-4-acetylpiperidine hydrochloride, m.p. 207-208 C., was prepared from 4-( 3 ,3 -dichloroallyl)-4-( 3 '-hydroxyphenyl )-4-acetylpiperidine and l-bromo-3,3-dichloropropene-(2). The yield was 2.3 g. (63 percent of theory).

EXAMPLE 60 Using a procedure analogous to that described in example 2, l-( 3 ,3 -dichloroallyl)- l 3 '-hydroxyphenyl)-4propionylpiperidine hydrochloride, m.p. 2l8-219 C., was prepared from 4-(3'-hydroxyphenyl)-4-propionyl-piperidine and lbromo-3,3-dichloropropene-(2). The yield was 2.75 g. (73 percent of theory).

EXAMPLE 61 Using a procedure analogous to that described in example l-( 3 ',3'-dichloroallyl )-4( 3 '-hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. l89-l90 C., was prepared from 4-(3'-hydroxyphenyl-4-methoxycarbonylpiperidine hydrochloride and l-bromo-3,3-dichloropropene- (2). The yield was 2.7 g. (71 percent of theory).

EXAMPLE 62 Using a procedure analogous to that described in example 5 1-( 3 ,3-dichloroallyl )-4( 3 '-hydroxyphenyl )-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 22l222 C., was prepared from 4-(3-hydroxyphenyl)-4-ethoxycarbonylpiperidine hydrochloride and 1-bromo-3,3-dichloropropene- (2). The yield was 3.0 g. (76 percent oftheory).

EXAMPLE 63 Using a procedure analogous to that described in example 2, 1-( 2 ,3 '-dichloroallyl )-4-( 3 '-hydroxyphenyl)-4-acetylpiperidine hydrochloride, m.p. 195-l98 C., was prepared from 4-(3'-hdyroxyphenyl)-4-acetyl-piperidine and 1,2,3- trichlorpropene-(2). The yield was 1.7 g. (46.5 percent of theory).

EXAMPLE 64 Using a procedure analogous to that described in example was prepared from 4-( 3 -hydroxyphenylfil acetyl-piperidine and cis-l ,3-dibromopropene-(2). The yield was '1 .8 g. (48 percent of theory).

EXAMPLE 65 Using a procedure analogous to that described in example 3 transl 3'-bromoallyl )-4-( 3 -hydroxyphenyl)-4-acetylpiperidine hydrochloride, m.p. l95-l97 C., was prepared from 4 -(3'-hydroxyphenyl)-4-acetyl-piperidine and trans-1,3- dibromopropene-(Z). The yield was 1.8 g. (48 percent of theory).

EXAMPLE 66 Using a procedure analogous to that described in example 4, cis- 1 3 '-bromoallyl )-4-( 3 '-hydroxyphenyl)-4-methoxycarbonybpiperidine hydrochloride, m.p. 197 C., was prepared from 4-(3-hydroxyphenyl)-4-methoxycarbony1- piperidine hydrochloride and cis-l,3-dibromopropene-(2). The yield was 2.4 g. (61.5 percent of theory).

EXAMPLE 67 Using a procedure analogous to that described in example 3 transl 3 '-bromoallyl)-4-( 3 '-hydroxyphenyl)-4methoxycarbonyl-piperidine hydrochloride, m.p. 212-214 C., was prepared from 4-(3'-hydroxypheny1)-4-methoxycarbonylpiperidine hydrochloride and trans-1,3-dibromopropene-(2). The yield was 2.6 g. (66.5 percent of theory).

EXAMPLE 68 Using a procedure analogous to that described in example 2, l-(2-bromoally1)-4-( 3 '-hydroxyphenyl )-4-acetylpiperidine hydrochloride, m.p. l79-l C., of the formula ll CCHa lir was prepared from 4-(3'-hydroxyphenyl)-4-acetyl-piperidine and 1,2-dibromopropene-(2). The yield was 2.6 g. (69.5 percent of theory).

EXAMPLE 69 Using a procedure analogous to that described in example 2, l-( 2'-bromoallyl)-4-( 3 '-hydroxyphenyl )-4-propionylpiperidine hydrochloride, m.p. l80-l8l C., was prepared from 4-(3-hydroxyphenyl)-4-propionyl-piperidine and 1,2- dibromopropene-(Z). The yield was 2.7 g. (70 percent of theory).

EXAMPLE 70 Using a procedure analogous to that described in example 5 l-( 2'-bromoallyl)-4-( 3 -hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. l89-l90 C., was prepared from 4-(3"-hydroxyphenyl)-4-methoxycarbonylpiperidine hydrochloride and 1,2-dibromopropene-(2). The yield was 2.6 g. (68.5 percent of theory).

EXAMPLE 71 Using a procedure analogous to that described in example 5 l-( 2-bromoallyl )-4-( 3 -hydroxyphenyl )-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 187 C., was prepared from 4-( 3 '-hydroxyphenyl )-4-ethoxycarbonyl-piperidine hydrochloride and l,2-dibromopropene-(2). The yield was 2.9 g. (72 percent of theory).

EXAMPLE 72 Using a procedure analogous to that described in example 2, 1-( 3 ,3 '-dibromoallyl)-4-( 3 '-hydroxyphenyl )-4-acetylpiperidine hydrochloride, m.p. 222 C., was prepared from 4- 3 -hydroxyphenyl )-4-acetyl-piperidine and l ,3 ,3- tribromopropene-(Z). The yield was 4.0 g. (88 percent of theory).

EXAMPLE 73 Using a procedure analogous to that described in example 2, l-(3', 3'-dibromoallyl)-4-(3-hydroxyphenyl)-4-propionylpiperidine hydrochloride, m.p. 233 C., was prepared from 4- (3 '-hydroxyphenyl)-4-propionyl-piperidine and 1,3 ,3- tribromopropene-(2). The yield was 4.0 g. (85.5 percent of theory).

EXAMPLE 74 Using a procedure analogous to that described in example 5, l-(3,3'-dibromoallyl)-4-(3"-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 207 C., was prepared from 4-(3'-hydroxyphenyl)-4-methoxycarbonylpiperidine hydrochloride and l,3,3-tribromopropene-(2). The yield was 4.2 g. (89.5 percent of theory).

119 EXAMPLE 75 Using a procedure analogous to that described in example 5, l-(3',3'-dibromoallyl)-4-(3"-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 219 C., was prepared from 4-( 3 '-hydroxyphenyl )-4-ethoxycarbonyl-piperidine hydrochloride and l,3,3-tribrompropene-(2). The yield was 3.95 g. (81.5 percent oftheory).

EXAMPLE76 Preparation of l-(3,3'-dimethylally1)-4-(3"-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride by method A 2.9 g. (0.01 mol) of 4-(3-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride were dissolved in cc. of water, the solution was admixed with 10 cc. of 2 N sodium hydroxide, and the alkaline solution was extracted with ether. The ether phase was dried over magnesium sulfate and was then evaporated. The residue was dissolved in a mixture consisting of 30 cc. of tetrahydrofuran and cc. of dimethylformamide, and to the resulting solution a mixture of 1.5 g. (0.01 mol) of 3,3-dimethylallyl-bromide and 1.3 g. (0.017 mol) of sodium bicarbonate was added. The mixture was refluxed for 9 hours, thereafter evaporated to dryness in an aspirator vacuum, the residue was stirred with a small amount of water to form a paste, and the paste was extracted with chloroform. The chloroform solution was dried over magnesium sulfate, evaporated to dryness, the residue was dissolved in methylene chloride which contained 2 percent of ethylacetate, and the resulting solution was filtered through 60 g. of basic aluminum oxide (activity I). The filtrate was evaporated, the residue was dissolved in 5 cc. of methanol, the solution was acidified with ethereal hydrochloric acid, and the acid solution was admixed with ether until it turned slightly cloudy, whereupon a crystalline precipitate formed which was separated and recrystallized from a mixture of methanol and ether. 3.2 g. (89 percent of theory) of a compound having a melting point of l-202 C. were obtained. It was identified to be l-(3,3'-dimethylallyl)-4 3 -chlorophenyl )-4-methoxycarbonyl-piperidine hydrochloride of the formula ll C-OCHa EXAMPLE 77 Using a procedure analogous to that described in example 76, l-(3', 3'-dimethylallyl)-4-(2"-methylphenyl)-4-acetylpiperidine hydrochloride, m.p. l75-l78 C., ofthe formula O CH:;

C-CH

L -HC1 1| /CHa CH2CH=C was prepared from 4- (2' rnethylphenyl)-4-acetyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.2 g. (60 percent of theory).

EXAMPLE 78 Using a procedure analogous to that described in example 76, l-(3',3-dimethylallyl)-4-(2"-methylphenyl)-4-propionylpiperidine hydrochloride, m.p. l86l88 C., was prepared from 4-(2-methylphenyl)-4-propionyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.6 g. (68 percent of theory).

EXAMPLE 79 Using a procedure analogous to that described in example 76,1 -(3',3'-dimethylallyl)-4-(3 '-methylphenyl )-4-acetylpiperidine hydrochloride, m.p. 204205 C., was prepared from 4-(3-methylphenyl)-4-acetyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.4 g. (75 percent of theory).

EXAMPLE 80 Using a procedure analogous to that described in example 76, l-(3'-,3'-dimethylallyl)-4-(3"-methylphenyl)-4-propionyl-piperidine hydrochloride, m.p. 209-2l2 C., was prepared from 4-(3'-methylphenyl)-4-propionyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.5 g. (74 percent of theory).

EXAMPLE 8 1 EXAMPLE 82 Using a procedure analogous to that described in example 76, l-( 3 ,3 '-dimethylallyl)-4-( 3 '-methylphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. l68-169 C., was prepared from 4-(3'-methylphenyl)-4-ethoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.4 g. (68 percent of theory).

EXAMPLE 83 Using a procedure analogous to that described in example 76, 1-(3', 3-dimethylallyl)-4-(4"-methylphenyl)-4-acetylpiperidine hydrochloride, m.p. 2092l0 C. of the formula ,L.L V.E 7.931;,

was prepared from 4-(4'-methylphenyl)-4-acetyl-piperidine hydrochloride and 3',3'-dimethylallyl.bromide. The yield was 2.2 g. (77 percent of theory). 1

EXAMPLE 84 Using a procedure analogous to that described in example 76, l-(3,3'-dimethylallyl)-4-(4"-methylphynyl)-4-propionylpiperidine hydrochloride, m.p. 193-l94 C., was prepared from 4-(4-methylphenyl)-4-propionyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.2 g. (74 percent of theory).

EXAMPLE 85 Using a procedure analogous to that described in example 76, l-( 3 ,3 '-dimethylallyl)-4-(4' '-methylphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. l97-l98 C., was prepared from 4-(4'-methylphenyl)-4-methoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The

yield was 3.0 g. (89 percent of theory).

EXAMPLE 86 Using a procedure analogous to that described in example 76, l-( 3 ,3 '-dimethylallyl)-4-(4' '-methylphenyl )-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 200-20l C., was prepared from 4-(4'-methylphenyl)-4-ethoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.2 g. (62 percent of theory).

EXAMPLE 87 Using a procedure analogous to that described in example 76, l-( 3 ,3 '-dimethylallyl )-4-( 2 '-chlorophenyl)-4-acetylpiperidine hydrochloride, m.p. 21 2-2l 3 C., of the formula C1 i ll was prepared from 4-(2'-chlorophenyl)-4-acetyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.1 g. (54 percent of theory).

EXAMPLE 88 Using a procedure analogous to that described in example 76, l-(3,3'-dimethylallyl)-4-(2" chlorophenyl)-4-propionylpiperidine hydrochloride, m.p. l 63-l64 C., was prepared from 4-(2'-chlorophenyl)-4-propionyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 3.6 g. (90 percent oftheory).

EXAMPLE 89 Using a procedure analogous to that described in example 76, 1-( 3 ,3 -dimethylallyl)-4 3 -chlorophenyl)-4-acetylpiperidine hydrochloride, m.p. 2 l 9-22 1 C., of the formula If C-CH:

-HCl

N CH3 HzCH=C was prepared from 4-(3-chlorophenyl)-4-acetyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 3.0 g. (88 percent of theory).

EXAMPLE 90 Using a procedure analogous to that described in example 76, l-( 3 ,3 -d.imethylallyl)-4( 3 "-chloropbenylM-propionylpiperidine hydrochloride, m.p. 2l32l5 C., was prepared from hydrochloride and 3,3- dimethylallyl bromide. The yield was 3.5 g. (98 percent of theory).

4-( 3 -chlorphenyl )-4-propionyl-piperidine 75 EXAMPLE 91 Using a procedure analogous to that described in example 76, l 3' ,3'-dimethylallyl)-4-( 3 '-chlorophenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. l72-l75 C., was prepared from 4-( 3 -chlorophenyl)-4-ethoxycarbonylpiperidine hydrochloride and 3,3-dirnethylallyl bromide. The yield was 3.7 g. (99 percent of theory).

EXAMPLE 92 Using a procedure analogous to that described in example 76,1-(3' ,3 -dlmethylallyl)-4-(4 -chlorophenyl)-4-acetylpiperidine hydrochloride, m.p. 2 l 22 14 C., of the formula was prepared from 4-(4'-chlorophenyl)-4-acetyl-piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 1.8 g. (59 percent oftheory).

EXAMPLE 93 Using a procedure analogous to that described in example 76, l-( 3 ,3 '-dimethylallyl)-4-( 4' '-chlorophenyl)4-propionylpiperdine hydrochloride, m.p. 205-206 C., was prepared from 4 -(4'-chlorophenyl)-4propionyl-piperdine hydrochloride and 3,3-dimethylallyl bromide. The yield was 3.3 g. (98 percent of theory).

EXAMPLE 94 Using a procedure analogous to that described in example 76, l-(3,3-dimethylallyl)-4-(4"-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 2142l6 C., was prepared from 4-(4"-chlorophenyl)-4-methoxycarbony|- piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.3 g. (64 percent of theory).

EXAMPLE 95 Using a procedure analogous to that described in example 76, l-(3',3'-dlmethylallyl)-4-(4"-chlorophenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 22l222 C., was prepared from 4-(4-chlorophenyl)-4-ethoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.8 g. percent of theory).

EXAMPLE 96 Using a procedure analogous to that described in example v 3,627,772 25 2. was prepared from 4-(2'-methylphenyl)-r4-acetyl-piperidine was prepared from 4-(4'-methylphenyl)-4-acetyl-piperidine hydrochloride and 2-methylallyl chloride. The yield was 2.9 g. hydrochloride and Z-methylallyl chloride. The yield was 2.7 g.

(82 percent of theory). (88 percent of theory).

EXAMPLE 97 5 EXAMPLE 103 Using a procedure analogous to that described in example Using a procedure analogous to that described in example 76, l-( 2 -methylallyl)-4-( 2 '-methylphenyl)-4-propionyl-' 76, 1 2'-methylallyl )-4-( 4' -methylphenyl )-4-propionylpiperidine hydrochloride, m.p. l94-l96 C., was prepared piperidine hydrochloride, m.p. 22022l C., was prepared from. 4-(2'-methylphenyl)-4-propionyl-piperidirle from 4-(4'-methylphenyl-4-propionyl-piperidine hydrochloride and 2-methylallyl chloride. The yield was 2.0 g. hydrochloride and Z-methylallyl chloride. The yield was 2.6 g. 55 percent of theory). (71 percent of theory).

EXAMPLE 9:; EXAMPLE 104 Using a procedure analogous to that described in example I Using a procedure analogous to that described in example 76, l-(2-rnethylallyl)-4)(3"-methylphenyD-4-acetyl- 76, l-(2-methylallyl)-4-(4"-methylphenyl)-4methoxycarpiperidine hydrochloride, m.p. l99-r20lC., of the formula bonyl-piperidine hydrochloride, m.p. 2l9-22l C., was "mmmww m pre ared from 4-(4'-methylphenyl)-4-methoxycarbonyl- CH? piperidine hydrochloride and 2-methylallyl chloride. The yield 0 was 2.5 g. (68 percent of theory). i l-@113 EXAMPLE 105 Using a procedure analogous to that described in example 76, l-(2'-methylallyl)-4-(4"-methylphenyl)-4-ethoxy carbonyl-piperidine hydrochloride, m.p. 2l9-22 1 C., was prepared N A from 4-(4'-methylphenyl)-4-ethoxycarbonyl-piperidine l hydrochloride and 2-methylallyl chloride. The yield was 2.5 g.

CH3(l3=CH2 (66 percent of theory.)

3o EXAMPLE 106 was prepared from 4-(3-methylphenyl)-4-acetyl-piperidine hydrochloride and Z-methylallyl chloride. The yield was 3.2 g. Usmg a pmcefilure analgus 9, desmbed example (91 percent oftheoryy 7 6, 1-(2 -methylallyl)-4-(3 -bromophenyl)-4-acetyl- 1 plperidlne hydrochloride, m.p. 22 l-223 C., of the formula EXAMPLE 99 Using a procedure analogous to that described in example 76, l-(2-methylallyl)-4-(3"-methylphenyl)-4-propionylpiperidine hydrochloride, m.p. 200-203 C., was prepared 7 C-OHa from 4-( 3 '-methylpheuyl)-4-propionyl-piperidine 1 hydrochloride and Z-methylallyl chloride. The yield was 1.2 g. 40 (37.3 percenttheory). -HCl EXAMPLE )0 Using a procedure analogous to that described in example E 76, l-(2-methylallyl)-4-(3"-methylpbenylM-methoxycarcm bon li eridine h drochloride, m. 230-232 C., was

pregarz from 4-(3'-methylpheri yl)-4-methoxycai'bonylwas f from bromophcfwl)'4'acqtyl'plpend;ne

piperidirle hydrochloride and 2-methylallyl chloride. The yield hydmchlmde and The was (78 percent of theory).

was 3.1 g. (84 percent of theory). 0

5 EXAMPLE 107 t th t d bed am le Uslng a procedure analogous to that described In example fj;jxgf ffigmjfffim a i fijfg glf g gg g g ggg gjg i gf' fg'zl'fi fg f iz yl-piperidine hydrochloride, m.p. 2l3-2 l4 C., was prepared Pp y p par from 4-(3'-bromophenyl)-4-methoXycarbonyl-piperidine EXAMPLE 101 from 4-(3'-methylphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 2-methylallyl chloride. The yield was 2.6 g. gg i i f The yeld was (77 percent of theory). Pace 0 any EXAMPLE 102 EXAMPLE 108 Usin d l m t d 1 Using a procedure analogous to that described in example 76 g a figr g i 13 3 1 a 76 1-(2'-methylallyl)-4-(4"-bromophenyl)-4-methoxycare y y-- -m yp ny -aceyo rie a'eeehzqseehadde.we2 %":29ii9rea i ned.,, liffif 2 1 8 CH3 Br l I? ll CCH3 C O C H:

.3161 I -HCl l CH2C=CH2 CH2(I'=CH:

CH 0H,

was prepared from 4-(4'-bromophenyl)-4-methoxycarb0nyl- V EXAMPLE-717175 prpegnme lgyadrochlozrd; and Z-methylallylchlonde. The yield Using a p lute analogous to that described in example was 8- Pflcen amy) 76. l-(2'-rnethylallyl)-4-(4"-chlorophenyl)-4- -propionylpiperidine hydrochloride, m.p. 230231 C., was prepared EXAMPLE 109 fI'Om 4-(4'-chlorophenyl)-4-propionyl-piperidine hd hl'd d2- thlalll Using a procedure analogous to that described in example 5 3 2 g r y y chlonde The ylcld was 2 9 g 76, l-(2'-methylallyl)-4-(2"-chlorophenyl)-4-acetylridineh drochloride, m. l48l50 C.,of the formula We y I p EXAMPLE 116 Using a procedure analogous to that described in example 76, l-(2' methylallyl)-4-(4"-chlorophenyl)-4-methoxy-carbonyl-piperidine hydrochloride, m.p. 2l72l8 C., was

0 prepared from 4-(4'-chlorophenyl)-4-methoxycarbonyl- 1- g piperidine hydrochloride and Z-methylallyl chloride. The yield c was 2.4 g. (79 percent of theory).

J {m EXAMPLE 117 N Using a procedure analogous to that described in example 76, l-(2methylally)-4-(4"-chlorophenyl)-4-ethoxycarbonyl- I piperidine hydrochloride, m.p. 22l-222 C., was prepared CH; 7 from 4-(4'-chlorophenyl)-4-ethoxycarbonyl-piperidine 25 hydrochloride and 2-methylallyl chloride. The yield was 2.6 g.

(73 percent of theory).

was prepared from 4-(2'-chlorophenyl)-4-acetyl-piperidine hydrochloride and Z-methylallyl chloride. The yield was 2.9 g. EXAMPLE 1 18 (75 percent oftheory) Using a procedure analogous to that described in example W n 76, 1-(2'-methylallyl)-4-(3"fluorophenyl)-4-methoxycarbon- EXAMPLE 1 l0 yl-piperidine hydrochloride, m.p. 2 l 5-2 1 6 C., of the formula Using a procedure analogous to that described in example 76, l-( 2'-methylallyl )-4-( 3 '-chlorophenyl)-4-acetyl- 3 5 piperidine hydrochloride, m.p. 226228 C., was prepared F- from 4-(3'-chlorophenyl)-4-acetyl-piperidine hydrochloride 0 and Z-methylallyl chloride. The yield was 3.2 g. (98 percent of II theory). C-OCH;

EXAMPLE 1 ll -HCl Using a procedure analogous to that described in example N 76, l-( 2'-methylallyl )-4-( 3 '-chlorophenyl )-4-propionyll piperidine hydrochloride, m.p. 2l5-2l7 C., was prepared Cube-CH from 4-(3'-chlorophenyl)-4-propionyl-piperidine hydrochloride and 2-methylallyl chloride. The yield was 2.3 g. (67 percent oftheory) was prepared from 4-(3-fluorophenyl)-4-methoxycarbonylpiperidine hydrochloride and Z-methylallyl chloride. The yield EXAMPLE 1 12 was 2.0 g. (61 percent of theory).

Using a procedure analogous to that described in example 76, l-(2methylallyl)-4-(3"-chlorophenyl)-4-methoxycarbon- EXAMPLE 119 yl-piperidine hydrochloride, m.p. 2l72l8 C., was prepared from 4-(3-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride and 2-methylallyl chloride. The yield was 2.3 g.

(67 percent of theory).

Using a'procedure analogous to that described in example 76, l-( l-methylally)-4-(3"-methylphenyl)-4methoxycarbonyl-piperidine hydrochloride, m.p. 209-2l 1C., of the formula EXAMPLE I13 CH:- Using a procedure analogous to that described in example w 76, l-( 2-methylallyl )-4-( 3 '-chlor0phenyl )-4-ethoxycarbon- E yl-piperidine hydrochloride, m.p. l88-l 89 C., was prepared CHI from 4-( 3 -chlorophenyl )-4-ethoxycarbonyl-piperidine hydrochloride and 2-methylallyl chloride. The yield was 2.5 g. percent of theory). L

EXAMPLE n4 (I]H CH=CH;

Using a procedure analogous to that described in example 70 Hz 76, l-(2'methylallyl)-4-(4"-chlorophenyl)-4-acetylpiperidine hydrochloride, m.p. 2l2-2l5 C., was prepared from p y ly 'p p hydl'mhlcfide was prepared from 4-(3'-methylphenyl)-4-methoxycarbonyland Z-methylallyl chloride. The yield was 2.0 g. (61 percent of piperidine hydrochloride and l-methylallyl chloride. The yield theory). was 2.0 g. (60 percent of theory).

. l EXAMPLE 120 Using a procedure analogous to that described in example 76, l-( l -methylallyl)-4-( 3' -methylphenyl )-4-ethoxycarbonyl-piperidine hydrochloride, m.p. l65-l67 C., was prepared from 4-( 3 -methylphenyl )-4-ethoxycarbonyl-piperidine hydrochloride and l-methylallyl chloride. The yield was 1.5 g.

(42 percent of theory).

EXAMPLE 121 Using a procedure analogous to that described in example 76, l-(3',3"dimethylallyl)-4-(3"-fiuorophenyl)-4-methoxycarbonyl-piperidine hydrobromide, m.p. 223-224 C., of the formula was prepared from 4-(3'-fluorophenyl)-4-methoxycarbonylpiperidine hydrochloride and 3,3dimethylallyl bromide. The yield was 2.8 g. (73 percent of theory).

EXAMPLE 122 Using a procedure analogous to that described'in example 76, l-( 3',3 -dimethylallyl )-4-(3 "-fluorophenyl)-4-ethoxycarbonyl-piper'idine hydrobrornide,- m.p. 205-206 C., was prepared from 4-( 3 fluorophenyl -4-ethoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 3.7 g. (92 percent of theory).

EXAMPLE 123 Using'a procedure analogous to thatdescribed in example M j r sn oa=crrcm was prepared from 4-(3'-methylphenyl)-4-methoxycarbonylpiperidine hydrochloride and 'y-methallyl bromide (l-bromo- Z-butene). The yield was 2.2 g. (60 percent of theory).

EXAMPLE 124 Using a procedure analogous to that described in example 76, I piperidine hydrobromide, m.p. l72l 75 C., of the formula l C 2H5 -HBr g I I I g -QFFQEQB l-crotyl-4r(3'-methoxyphenyl)-4-ethoxycarbonyl- 28 was. prepared from 4-( 3'-methoxyphenyl) 4-ethoxycarbonylpiperidine hydrochloride and y-methallyl bromide. The yield was 1.6 g. (42 percent of theory).

EXAMPLE 125 Using a procedure analogous to that described in example 76, l-crotyl-4( 3 '-fluorophenyl )-4-m'ethoxycarbonylpiperidine hydrobromide, m.p. 2 l 2-2 14 C., of the formula was prepared from 4-(3-fluor;phenyl)-4-methoxycarbonylpiperidine hydrochloride and 'y-methallyl bromide. The yield was2.l g. (56 percent oftheory).

EXAMPLE 126 Using a procedure analogous'to that described in example I l-crotyl-4-(3'-chlorophenyl)-4-acetyl-piperidine hydrobromide, m.p. l98-200 C., was prepared from 4-(3'- chlorophenyl)-4-acetyl piperidine hydrochloride and ymethallyl bromide. The yield was 2.2 g. (59 percent of theory).

' EXAMPL 127 Using a procedure analogous to that described in example 76, Y l-crotyl-4-( 3 '-chlorophenyl)-4-methoxycarbonylpiperidine hydrobromide, mlp. 2l l-2l3 C., was prepared from hydrochloride and y-methallyl bromide-The yield was 2.2

(5 7 percent of theory).

EXAMPLE 1 28' Using a procedure analogous to that described in example 76, l-crotyl-4-(3'chlorophenyl)-4-ethoxycarbonyl-piperidine 4hydrobromide, m'.p. l72-l75 C., was prepared from 4-(3'- hydrochloride chlorophenyl)-4-ethoxycarbonyl-piperidine and 'y-methallyl bromide. The yield was 2.1 g. (52

percent of theory). 1

EXAMPLE 129 Using a procedure analogous to that described in example 76, l-crotyl-4-(4'-chlorophenyl)-4-ethoxycarbonyl-piperidine hydrobromide, m.p. 200-202 C., was prepared from 4-(4'- chlorophenyl)-4-ethoxycarbonyl-piperidinev hydrochloride and 'y-methallyl bromide. The yield was 2.2 g. (55 percent of theory).

EXAMPLE Using a procedure analogous to that described in example I 76, l-( l ',-methylallyl)-4-(4"-chlorophenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. l99-200 C., was prepared from 4-(4"-chlorophenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 3-chlorobutene-(l). The yield was 0.9 g. (25 percent of theory).

EXAMPLE l3 1 Preparatiqnof 1-.(3', 3'-dimethylallyl)-4-(3"-hydroxyphen. y

I 4-acetyl-piperidine hydrochloride by method A 2.18 g. (0.01 mol) of 4-(3-hydroxyphenyl-4-acetylpiperidine, 1.26 g. (0.015 mol) of sodium bicarbonate, 1.64 g. of 3,3-die'mthylallyl bromide, 10 cc. of dimethyl formamide 4-(3'-chlorophenyl)-4-methoxycarbonyl-piperidine 29 and 25 cc.- of tetrahydrofuran were admixed with each other, and the mixture was refluxed for 2 hours. Thereafter, the solvent medium was evaporated in vacuo, and the residue was rinsed with 50 cc. of chloroform into a separating funnel. The chloroform solution was extracted three times with 20 cc. portions of water, dried over sodium sulfate, and evaporated in vacuo. The residue was taken up in methanol, the resulting solution was acidified with 4 cc. of 2.5 N ethanolic hydrochloric acid, and the acid solution was admixed with ether until it turned cloudy. Upon scratching, a crystalline precipitate separated out. The precipitate was separated by vacuum filtration the following morning, washed with water and dried. 1.3 g. (40 percent of theory) of a compound having a melting point of 195 C., were obtained. It was identified to be 1-(3' ,3 '-dimethylallyl)-4-( 3 -hydroxyphenyl )-4-acetyl-piperidine hydrochloride of the formula ll C-CH;

EXAMPLE 132 Preparation of 1-(3,3'-dimethylallyl)-4-(3"-hydroxyphenyl)- 4-ethoxycarbonyl-piperidine hydrochloride by method A 2.86 g. (0.01 mol) of 4-(3'-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, 2.10 g. (0.025 mol) of sodium bicarbonate, 1.64 g. (0.011 mol) of 3,3-dimethylallyl bromide, 10 cc. of dimethylformamide and 25 cc. of

0 97-0 CrHs EXAMPLE 133 Using a procedure analogous to that described in example 131, l-(3',3'-dimethylallyl)-4-(3"-hydroxyphenyl)-4-propio- 132,

. methoxycarbonyl-piperidine hydrochloride, m.p. 198 C., was 7 prepared from 4-(4-hydroxyphenyl)-4-methoxycarbonylnyl-piperidine hydrochloride, m.p. 217 C., was prepared from 4-( 3 -hydroxyphenyl)-4-propionyl-piperidine and 3,3- dimethylallyl bromide. The yield was 1.7 g. (50.5 percent of theory).

EXAMPLE 134 (3'-hydroxyphenyl)-4-butyryl-piperidine hydrochloride and 75 rn 1lg MW 3,3-dimethylallyl bromide. The yield was 2.0 g. (57 percent of theory).

EXAMPLE 135 v 0 piperidine hydrochloride and 3,3-dimethylallyl bromide. The

yield was 1.5 g. (44 percent of theory).

EXAMPLE 136 Using a procedure analogous to that described in example 1 32, 1-( 3' ,3 '-dimethylallyl)-4-( 3 '-hydroxyphenyl)-4-propoxycarbonyl-piperidine hydrochloride, m.p. 214 C., was prepared from 4-(3'-hydroxyphenyl)-4-propoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 1.7 g. (47.5 percent of theory).

EXAMPLE 137 Using a procedure analogous to that described in example 132, l-(3',3-dimethylallyl)-4-(3"-methoxyphenyl)-4-propid nyl-piperidine hydrochloride, m.p. 165 C., of the formula was prepared from 4-(3'-methoxyphenyl)-4-propionylpiperidine and 3,3-dimethylallyl bromide. The yield was 1.8 g. t (51 percent of theory).

EXAMPLE 138 Using a procedure analogous to that described in example 1 32, 1-( 3',3'-dimethy1allyl)-4-(3"-methoxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 171 C., was prepared from 4-(3-methoxyphenyl)-4-ethoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 2.0 g. (54.5 percent of theory).

EXAMPLE 139 Using a procedure analogous to that described in example 132, l-( 3 ',3-dimethylallyl )-4-( 2' '-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 230 C., was prepared from 4-(2-hydroxyphenyl)-4-methoxycarbonylpiperidine hydrochloride and 3,3-dimethylallyl bromide. The i yield was 2.0 g. (59 percent of theory).

EXAMPLE 140 Using a procedure analogous to that described in example l-(3,3'-dimethylallyl)-3a4(4"-hydroxyphenyl)-4- piperidine hydrochloride and 3,3-dimethylallyl bromide. The yield was 1.44 g. (42 percent of theory).

EXAMPLE 141 Using a procedure analogous to that described in example 131, 1-( 3' ,3 '-dimethylallyl-3a-methyl-4( 3 '-hydroxyphenyl)- 4-propionyl-piperidine hydrochloride, m.p. 83 C., of the forwas prepared from 3a-methyl-4-( 3-hydroxyphenyl)-4- propionyl-piperidine and 3,3-dimethylallyl bromide. The yield was 1.8 g. (51 percent oftheory).

EXAMPLE 142 Using a procedure analogous to that described in example 1 3 2, 1-( 3 ,3 '-dimethylallyl )-3a-methy1-4-( 3 -hydroxyphenyl 4-methoxycarbonyl-piperidine hydrochloride, m.p. 142 C., was prepared from 3a-methyl-4-(3-hydroxyphenyl)-4- methyoxycarbonyl-piperidine hydrochloride and 3,3- dimethylallyl bromide. The yield was 1.9 g. (53.5 percent of th y.

EXAMPLE 1E Using a procedure analogous to that described in example 1 32, l -crotyl4-( 3 '-hydroxyphenyl)-4-methoxycarbonylpiperidine hydrochloride, m.p. 213 C., was prepared from 4- 3 '-hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride and 'y-methally] bromide (reflux time: 3 hours). The yield was 1.7 g. (53.5 percent of theory).

EXAMPLE 144 Using a procedure analogous to that described in example 1 32, 1-crotyl-4-( 3 '-hydroxypheny1)-4-ethoxycarbonylpiperidine hydrochloride, m.p. 216 C., was prepared from 4- 3 '-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 'y-methallyl bromide (reflux time: 4 hours). The yield was 2.2 g. (64.5 percent of theory).

EXAMPLE 145 Using a procedure analogous to that described in example 1 32, 1 -crotyl-4-( 3 -hydroxyphenyl )-4-propoxycarbonylpiperidine hydrochloride, m.p. 210 C., was prepared from 4- 3 '-hydroxyphenyl )-4-propoxycarbonyl-piperidine hydrochloride and 7-methallyl bromide (reflux time: 3 hours). The yield was 2.5 g. (70.5 percent of theory).

EXAMPLE 146 Using a procedure analogous to that described in example 1 32, l-( 2'-methylallyl)4-( 3 '-hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride, m.p. 185 C., was prepared from 4-( 3 '-hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride and Bmethal1yl chloride (reflux time: 3 hours). The yield was 2.2 g. (67.5 percent of theory).

EXAMPLE 147 Using a procedure analogous to that described in example 132, 1-( 2-methylallyl)-4-( 3 -hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 173 C., was prepared from 4-( 3 '-hydroxyphenyl )-4-ethoxycarbony1-piperidine hydrochloride and B-methallyl chloride (reflux time: 3 hours). The yield was 2.7 g. (79.5 percent of theory).

EXAMPLE 148 Using a procedure analogous to that described in example 1 32, 1-( 2-methylal1yl)-4( 3 '-hydroxyphenyl )-4-propoxycarbonyl-piperidine hydrochloride, m.p. 150 C., was prepared from 4-(3'-hydroxypheny1)-4-propoxycarbonyl-piperidine hydrochloride and fi-methallyl chloride (reflux time: 3 hours). The yield was 2.6 g. (73.5 percent of theory).

EXAMPLE 149 Using a procedure analogous to that described in example 1 3 1 l-crotyl-4-( 3 -hydroxyphenyl )4-acetyl-piperidine hydrochloride, m.p. 162 C., was prepared from 4-( 3'-hydroxyphenyl)-4-acetyl-piperidine and 'y-methallyl bromide (reflux time: 3 hours). The yield was 1.1 g. (35.5 percent of theory).

EXAMPLE 150 Using a procedure analogous to that described in example 1 3 1, l-crotyl-4-( 3 '-hydroxyphenyl )4-propionyl-piperidine hydrochloride, m.p. 209 C., was prepared from 4-(3'-hydroxyphenyl)-4-propionyl-piperidine and 'y-methallyl bromide (reflux time: 3 hours). The yield was 2.2 g. (68 percent of theory). 1

EXAMPLE 15 1 Using a procedure analogous to that described in example 13 l 1-crotyl-4-(3'-hydroxypheny1)-4-butyryl-piperidine hydrochloride, m.p. 2l5.5 C., was prepared from 4-(3- hydroxyphenyl)-4-butyryl-piperidine and 'y-methallyl bromide (reflux time: 3 hours). The yield was 1.75 g. (52 percent of theory).

EXAMPLE 152 .Using a procedure analogous to that described in example 1 3 l 1-( 2'-methylallyl )-4-( 3 '-hydroxyphenyl )-4-acetylpiperidine hydrochloride, m.p. 120 C., was prepared from 4- (3'-hydroxyphenyl)-4-acetyl-piperidine and B-methallyl chloride (reflux time: 3 hours). The yield was 2.2 g. (71 percent of theory).

EXAMPLE 1 5 3 Using a procedure analogous to that described in example 131, l-( 2-methylallyl )-4-( 3 '-hydroxyphenyl)-4-propionylpiperidine hydrochloride, m.p. 177 C., was prepared from 4- (3'-hydroxyphenyl)-4-propionyl-piperidine and fl-methallyl chloride (reflux time: 3 hours). The yield was 1.7 g. (52.5 percent of theory).

EXAMPLE 154 Using a procedure analogous to that described in example 13 1, l( 2 '-methylallyl )-4-( 3 '-hydroxyphenyl )-4-butyrylpiperidine, m.p. 192 C., was prepared from 4-(3'-hydroxyphenyl)-4-butyryl piperidine and ,B-methallyl chloride (reflux time: 3 hours). The yield was 1.7 g. (50 percent of theory).

EXAMPLE 155 Using a procedure analogous to that described in example 1 32, l-croty1-4-( 2' '-hydroxyphenyl)-4-ethoxycarbonylpiperidine hydrochloride, m.p. 222 C., was prepared from 4- 2 '-hydroxyphenyl )4-ethoxycarbonyl-piperidinehydrochloride and B-methallyl chloride (reflux time: 3 hours). The yield was 1.4 g. (41 percent of theory).

EXAMPLE 156 Using a procedure analogous to that described in example 132, 1-( 2'-methylallyl)-4-( 2' '-hydroxyphenyl )-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 248 C., was prepared from 4-(2'-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and B-methallyl chloride (reflux time: 3 hours). The yield was 2.8 g. (82.5 percent of theory).

EXAMPLE 157 Using a procedure analogous to that described in example 132, 1-crotyl-4-(4'-hydroxyphenyl)-4-ethoxycarbonylpiperidine hydrochloride, m.p. 180.5 C., was prepared from 4-(4-'-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and 'y-methallyl bromide (reflux time: 3 hours). The yield was 2.85 g. (84 percent of theory).

EXAMPLE 158 Using a procedure analogous to that described in example 132, l-(2'-methylallyl)-4-(4"-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 212 C, was prepared from 4-(4'-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and B-methallyl chloride (reflux time: 3 hours). The yield was 1.6 g. (47 percent of theory).

EXAMPLE 159 Using a procedure analogous to that described in example 1 3 l 1-( l -methylally1)-4( 3 '-hydroxyphenyl)-4-propionylpiperidine hydrochloride, m.p. 210 C., was prepared from 4- (3'-hydroxyphenyl)-4-propionyl-piperidine and oz-methallyl chloride (reflux time: hours). The yield was 1.75 g. (54 percent of theory).

EXAMPLE 160 Using a procedure analogous to that described in example 132, l-( 1 -methylal1y1)-4-(3"-hydroxypheny1)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 199 C., was prepared from 4-(3-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride and a-methallyl chloride (reflux time: 15 hours). The yield was 2.5 g. (77 percent of theory).

EXAMPLE 161 Using a procedure analogous to that described in example 1 32, l-( l '-methylallyl)-4-( 2 -hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride, m.p. 226 C., was prepared from 4-(2'-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride and a-methal1yl chloride (reflux time: 15 hours). The yield was 1.9 g. (56 percent of theory).

EXAMPLE 162 with 75 cc. portions of toluene. The combined toluene extract solutions were dried with potassium carbonate, and then the toluene was distilled off at about 40-50 C. The residue was dissolved in 160 cc. of absolute toluene, and the resulting solution was admixed with 37.7 g. (0.256mo1) of 3-methoxybenzyl-cyanide. To the resulting mixture 21.2 g. (0.545 mol) of sodium amide were added in small portions over a period of 20 minutes while stirring and cooling with ice to maintain a temperature of 30-40 C. Thereafter, the reaction mixture was refluxed for 1 hour. Subsequently, the reaction solution was allowed to cool, admixed with 100 cc. of water, and the toluene phase was separated. The toluene solution was shaken with 200 cc. of 2 N HCl and 1,000 cc. of water until two clear liquid phases had formed, and the phases were separated. The aqueous phase was extracted first with toluene and then with ether, and was then made strongly alkaline with concentrated ammonia. The precipitate formed thereby, namely, the free base transl 3 -chloroallyl )-4-( 3 '-methoxyphenyl)-4-cyanopiperidine, was separated by extracting the mixture three times with 200 cc., portions of ether, and the combined extract solutions were dried with sodium sulfate and then acidified with ethanolic hydrochloric acid. The precipitate formed thereby was separated and washed with ether. Fifty-six grams (67 percent of theory) of the hydrochloride of the above free base were obtained. It had a melting point of 187 C.

b. Trans-l-(3'-chloroallyl)-4-(3-hydroxyphenyl)-4-carboxypipericline A mixture of 25 g. (0.074 mol) of trans-l-(3'-chloroa1lyl)- 4-(3"-methoxyphenyl)-4-cyano-piperidine hydrochloride, 42 g. of phenol and 190 cc. of aqueous 48 percent hydrobromic acid was refluxed for 4 hours. Thereafter, the reaction solution was allowed to cool, was then diluted with 190 cc. of water, and was extracted twice with cc. portions of ether. The combined ether extract solutions were washed with 50 cc. of water, the combined acid aqueous wash solutions were extracted once with 100 cc. of ether and then evaporated to dryness. The residue was recrystallized from water, yielding 18 g. (64.5 percent of theory) of the pure hydrobromide of trans-1- (3 -chloroally )-4-( 3 '-hydroxyphenyl-4-carboxy-piperidine having melting points of C. and 222 C. A small sample of the product, recrystallized from a mixture of I ethanol an ethanol and ether, had a melting point of 222 C.

The hydrobromide was dissolved in 225 cc. of water, and the solution was neutralized (pH 7) with concentrated ammonia, whereby the free base was liberated. It had a melting point of 273 C.

c. Trans- 1 3 '-chlo roallyl)-4-( 3 "-hydroxyphenyl )-4-methoxycarbonyl-piperidine hydrochloride 5.! g. (0.0172 mol) of trans-l-(3-ch1oroa1ly1)-4-(3"- hydroxyphenyl)-4-carboxy-piperidine were suspended in 50 cc. of absolute ethanol. The suspension was then placed on a boiling water bath and was saturated with dry hydrogen chloride gas. The suspended matter went into solution and later a precipitate formed. After boiling the mixture in this manner for 3 hours while passing hydrogen chloride therethrough, it was allowed to cool and the precipitate was separated by vacuum filtration. The crystalline filter cake was washed with a mixture of methanol and ether. 4.1 g. (83.5 percent of theory) of trans-l-(3'-chloroallyl)-4-(3-chloroallyl)- 4-( 3 '-hydroxypheny1)-4-methoxycarbonyl-piperidine hydrochloride, m.p. 217 C., were obtained.

The free base, obtained by neutralizing a solution of the hydrochloride with ammonia, had a melting point of 141 C.

EXAMPLE 163 Preparation of transl 3 -chloroally)-4-( 3 '-hydroxyphenyl)-4-acetyl-piperidine hydrochloride 25.0 g. (0.074 mol) of trans-l-(3'-chloroallyl)-4-(3"- methoxyphenyl)-4-cyano-piperidine hydrochloride, i.e., the product of example 162 (a), were shaken with a mixture of 100cc. water, 37 cc. 2 N sodium hydroxide and 75 cc. benzene, the benzene phase was separated, and the aqueous phase was extracted twice with 75 cc. portions of benzene. The benzene solutions were combined, dried with sodium sulfate, and the benzene was evaporated in vacuo. The residue was dissolved in absolute benzene, the solution was again evaporated to dryness, the residue was again dissolved in absolute benzene, and the resulting solution was added dropwise to a Grignard reagent consisting of a solution of methyl magnesium iodide in benzene at 40 C. Thereafter, benzene was distilled out of the reaction mixture, while stirring, until the internal temperature rose to 76 C., and then the mixture was stirred at that temperature for 16 hours. Subsequently, the reaction mixture was poured into a mixture of 200 g. ice and 50 g. ammonium chloride, heated to 30 C., and extracted three times with 200cc. portions of benzene. The combined benzene extract solutions were dried, and the benzene was evaporated. The residue was the 4-ketimine analog of the starting material, which was used without further purification in the subsequent reaction steps as follows:

50 grams of phenol and 220 cc. of aqueous 48 percent hydrobromic acid were added to the ketimine, and the mixture was refluxed for four hours, allowed to cool, diluted with 220 cc. of water and extracted twice with 100 cc. portions of ether. The ether extract solution was washed with 50 cc. of water, the wash solution and the extracted aqueous reaction solution were combined, again extracted with 100 cc. of ether and finally evaporated to dryness. The residue was dissolved in ethanol, and the solution was acidified with ethanolic hydrochloric acid, whereby a crystalline precipitate was formed. The precipitate was recrystallized from a mixture of ethanol and ether, yielding 7.4 g. (30.5 percent of theory) of trans l 3 '-chloroallyl )-4-( 3 -hydroxyphenyl )-4-acetylpiperidine hydrochloride, m.p. 184 C.

The trans-N-(3'-chloroallyl)-bis-(2"-chloroethyl)-amine hydrochloride used as a starting compound in example 162 was itself prepared in the following manner:

EXAMPLE 164 a. Trans-N-(3-chloroallyl)-diethanolamine 36.8 g. (0.35 mol) of diethanolamine, 42.5 g. (0.385 mol) of trans-l,3-dichloropropene-(2) and 44 g. (0.525 mol) of sodium bicarbonate were admixed with 43 cc. of dimethylformamide and I07 cc. of tetrahydrofuran, and the mixture was refluxed for 3 hours. Thereafter, the reaction solution was evaporated and the residue was shaken with a mixture of 100 cc. water and 75 cc. chloroform. The aqueous and organic phases were separated in a separating funnel, the aqueous phase was again extracted several times with 50 cc. portions of chloroform, the chloroform solutions were combined, dried over sodium sulfate, the solvent was distilled off, and the oily residue was distilled in vacuo. After a preliminary fraction of 6 g., 55.5 g. (88 percent of theory) of trans-N-(3-chloroallyl)- diethanolamine, b.p. l34-l36 C., at 0.4 mm. Hg, were obtained.

b. Trans-N-( 3-chloroallyl)-bis-( 2-dichloroethyl)-amine hydrochloride 46.0 g. (0.256 mol) of trans-N-( 3-chloroallyl)- diethanolamine were dissolved in 50 cc. of absolute chloroform, and the resulting solution was admixed over a period of thirty minutes with a solution of 130 g. of thionylchloride (1.1 mol) in 100 cc. of chloroform, accompanied by stirring and cooling with ice. Thereafter, the reaction mixture was refluxed for 1 hour, cooled and admixed with 300 cc. of absolute ether, The mixture was allowed to stand in a refrigerator, whereupon a crystalline precipitate separated out. The precipitate was separated, washed with ether, dried in vacuo and recrystallized from a mixture of ethanol and ether. 64 gram (100 percent of theory) of trans-N-(3- chloroallyl)-bis-(2"-chloroethyl)-amine hydrochloride, mp. 62 C., were obtained.

The compounds according to the present invention, that is, those embraced by formula I above and their nontoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit analgesic as well as morphine-antagonistic properties in warmblooded animals. In other words, they are very effective analgesics free from physical dependence capacity.

The morphine-antagonistic activities of the compounds of the present invention were ascertained by standard pharmacological tests on laboratory mice, as well as by tests on morphine-addicted monkeys.

For determination of the morphine-antagonistic activity in mice, mgJltg. of morphine, i.e., the median effective analgesic dose (ED which causes 50 percent of the test animals to show analgesic response in the test method of Hafiner, Deutsche Medizinische Wochenschrift 55, 751-733 (1929), for determination of analgesic activity, were subsutaneously injected into adult laboratory mice. Thereafter, the test compound under investigation for morphine-antagonistic activity was also injected subcutaneously at various dosage levels, and the dose range was determined which produces discernable to complete suppression of the morphine-induced analgesia. Ten mice were used for each dose of each of the compounds under investigation; the following illustrative results were obtained:

A l-(3"-Dimethylallyl)-4-(3"-hydroxyphenyD-Q4- ethoxycarbonyl-piperidine hydrochloride(example 132);

B== 1-( 3 ',3 '-Dimethylallyl )-4-( 3 '-methylphenyl)-4-ethoxycarbonyl-piperidine hydrochloride (example 83);

C l 3 ',3 '-DimethylaIlyl)-4-( 3 '-chlorophenyl )-4- methoxycarbonyl-piperidine hydrochloride (example 77);

l-( 3 ,3 -Dimethylallyl )-4-( 3 '-methylphenyl )-4-propionyl-piperidine hydrochloride (example 81 and E l-(3',3-Diemthyla.llyl)-4-phenyl-4propionlylpiperidine hydrochloride.

Percentage of test animals showing analgesic response Injection I5 rug/kg. morphine +0.l mg/kg. D ISmgJkg. morphine +0.3 mgJkg. D l5 mgJkg. morphine +1.0 mgJkg. D

15 mgJkg. morphine mg./kg. E 70 These results clearly show that the compounds of the instant invention (A-D) are efiective morphine antagonists, whereas the analogous compound with an unsubstituted 4-phenyl moiety instead potentiates the morphine analgesia and therefore is not a morphine antagonist.

Tests on morphine-addicted monkeys have shown that the compounds of the present invention. namely l-(3',3'- dimethylallyl)-4-( 3 '-methylphenyl )-4-ethylcarbonylpiperidine hydrochloride (NIH 8233), l-(3,3-diemthylallyl)- 4-( 3 '-hydroxyphenyl)-4-ethyIcarbonyl-pipiperidine methanesulfonate (NIH 8235) and l-( 340,3-dimethylally)-4- (3 '-hydroxy-phenyl )-4-ethoxycarbonyl-piperidine methanesulfonate (NIH 8169), are morphine-antagonists (see Report of the Committee on Problems of Drug Dependence, I966, Addendum 2, pages 8 and 9; and Report of the Committee on Drug Addiction and Norcotics, 1965, Addendum, page 9); on the other-hand, corresponding tests have shown that the prior art analogs, namely l-allyl-4-phenyl-4-carbopropoxypiperidine (NIH 7947) and l-allyl-4-phenyl-4-carbomethoxypiperidine (NII-I 7946), exhibit no morphine-antagonistic activities in morphine-addicted monkeys (see Bulletin of Drug Addition and Narcotics, 1962, Addendum 2, pages l3and 14.

For pharmaceutical purposes the compounds of the invention are administered to warmblooded animals perorally, parenterally or by the rectal route as active ingredients in customary dosage unit compositions, that is, in compositions in dosage unit form consisting essentially of an inert carrier and one dosage unit of the active ingredient, such as tablet, coated pills, suppositories, emulsions, suspensions, syrups, hypodermic solutions and the like. One dosage unit of a compound according to the present invention is from 0.166 to 5.0 mgJkg. preferably from 0.83 to 2.5 mg./kg.

The following examples illustrate a few dosage unit compositions comprising a compound of the present invention as w an active ingredient. The parts are parts by weight unless other wise specified.

EXAMPLE I65 l-lypodermic solution The solution was compounded from the following ingredients:

Trans- 1 3'-chloroallyl)-4-( 3"-hydroxyphenyl)-4methoxycarbonyl-piperidine hydrochloride l00.0 parts Dextrose l0.0 Distilled water q.s.nd by vol. 2,000.0 parts Compounding procedure:

EXAMPLE 166 Tablets The tablet composition was compounded from the following ingredients:

t-ethoxycarbonyl-piperidine hydrochloride 50.0 parts Corn starch 30.0 parts Lactose 20.0 parts Colloidal silicic acid 2.0 parts Gelatin 3.0 parts Magnesium stearate 2.0 parts Talcum 3.0 parts Total I l0.0 parts Compounding procedure:

The individual components were intimately admixed with each other, and the mixture was compressed into 110 mg. tablets. Each tablet contained 50 mg. of the piperidine compound and, when administered perorally to a warmblooded animal of about 60 kg. body weight in need of such treatment, produced very good analgesic effects.

EXAMPLE 167 Drop solution for oral administration The solution was compounded from the following ingredients:

Transl 3'-chloroallyl)-4-(3"-hydroxyphenyl)-4-rnethoxycarbonyl-piperidine hydrochloride 10.0 parts p-Hydroxybcnzoic acid methyl ester 0.07 parts p-Hydroxybenzoic acid propyl ester 0.03 pans Ethanol 20.0 parts Polyethyleneglycol 400 20.0 parts Demineralized water q.s.ad 100.0 parts by vol.

Compounding procedure:

The individual ingredients were dissolved in the water, and the solution was filtered. Each centimeter of solution (about five drops) contained 100 mg. of the active ingredient and, when administered perorally to a warmblooded animal of about 60 kg. body weight in need of such treatment, produced very good analgesic effects.

EXAMPLE 168 Suppositories The suppository composition was compounded from the following ingredients:

4-ethoxycurbonyl-piperidine hydrochloride l50.0 parts Lactose 150.0 parts Cocoa butter 1,400.0 parts Total 1,700.0 parts Compounding procedure:

The piperidine compound and the lactose were admixed with each other, and the mixture was uniformly blended into the molten cocoa butter. The mixture was then poured into cooled suppository molds, each holdin 1,700 mg. of the mixture. Eac suppository contained 15 mg. of t e piperidine compound and, when administered bythe rectal route to a warmblooded animal of about 60 kg. body weight in need of such treatment, produced very good analgesic effects.

Analogous results were obtained when any other compounds of the present invention was substituted for the particular piperidine compound in illustrative example l65 to 168. Likewise. the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to those particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of stereoisomeric mixtures of N y-chloroallyl-4-phenyl-4-ethoxycarbonyl-piperidine derivatives of the formula O -OCrHb JHr-CH=CHC1 wherein R is selected finfi gfiiipconsisting of hydroxy, methoxy and acetoxy; cis-stereoisomers of said piperidine derivatives, trans-stereoisomers of said piperidine derivatives; nontoxic, pharmacologically acceptable acid addition salts of said stereoisomeric mixtures; nontoxic, pharmacologically acceptable acid addition salts of said cis-stereoisomers; and nontoxic, pharmacologically acceptable acid addition salts of said trans-stereoisomers.

2. A compound according to claim 1, which is 1-(3'- chloroallyl )-4-( 3 "-hydroxyphenyl )-4-ethoxycarbonylpiperidine hydrochloride.

3. Trans- 1 3 '-chloroallyl)-4-( 3 -hydroxyphenyl )-4- methoxycarbonyl-piperidine hydrochloride.

4,. l-(3-chloroallyl)-4-(3"-hydroxyphenyl)-4-propionylpiperidine hydrochloride.

5. Cisl 3 '-chloroallyl )-4-( 3 -hydroxyphenyl)-4-methoxylcarbonyl-piperidine hydrochloride.

6. Trans- 1 3 '-chloroallyl )-4- 2 -chlorophenyl )-4-propionyl-piperidine hydrochloride.

7. l-( 3'-chloroallyl)-4-(3' -chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride.

i i t l 

2. A compound according to claim 1, which is 1-(3-chloroallyl)-4-(3-hydroxyphenyl)-4-ethoxycarbonyl-piperidine hydrochloride.
 3. Trans-1-(3-chloroallyl)-4-(3-hydroxyphenyl)-4-methoxycarbonyl-piperidine hydrochloride.
 4. 1-(3-Chloroallyl)-4-(3-hydroxyphenyl)-4-propionyl-piperidine hydrochloride.
 5. Cis-1-(3-chloroallyl)-4-(3-hydroxyphenyl)-4-methoxylcarbonyl-piperidine hydrochloride.
 6. Trans-1-(3-chloroallyl)-4-(2-chlorophenyl)-4-propionyl-piperidine hydrochloride.
 7. 1-(3-chloroallyl)-4-(3-chlorophenyl)-4-methoxycarbonyl-piperidine hydrochloride. 